PROJECT SUMMARY ? BASIC TRANSLATIONAL PROJECT Genetic variants in genes encoding proteins involved with drug elimination or drug target pathways contribute substantially to variable efficacy and may explain adverse drug reactions. Genetically-based variability in drug responses (efficacy and toxicity) is often explained by genes affecting the plasma or tissue drug concentration (pharmacokinetics) or its direct effects on the intended molecular target (pharmacodynamics). In this basic/translational project, we propose to investigate the impact of genomic variability on inter-individual differences in dosing, pharmacokinetics and pharmacodynamics of 3 selective serotonin reuptake inhibitorS (SSRIs; sertraline, fluoxetine, citalopram/escitalopram) used during pregnancy. Our focus will be on genes involved in the metabolism and elimination of SSRIs, transporters involved with removal of drug from the central nervous system, and genes encoding critical SSRI targets involved with therapeutic efficacy. Results from our study will inform whether pharmacogenomic testing can be implemented to improve outcomes in pregnant women receiving SSRIs and support individualized drug dosing across pregnancy and after birth. In Specific Aim 1, we will genetically classify subjects enrolled in the main clinical phase of the study by drug metabolizer phenotype, and then determine if phenotype is associated with SSRI pharmacokinetic parameters. The genotyping studies proposed in Specific Aim 1, will also contribute to the overall success of the Center by enabling us to stratify enrolled subjects by drug metabolizer phenotype and to ensure inclusion of sufficient numbers of subjects with less common metabolizer phenotypes (e.g., poor metabolizers and ultra-rapid metabolizers). In Specific Aim 2, we will determine if genomic variants in the serotonin transporter gene (SLC6A4), encoding the main target of SSRI drugs, are associated with likelihood of recurrence of major depressive disorder (MDD) during and after pregnancy. Correlations will be tested between genotype and measures of depression obtained by work performed in the main clinical project. We will restrict this analysis to the subgroup of subjects predicted to be extensive metabolizers to avoid the potential confounding influence of variable SSRI metabolism. Finally in Specific Aim 3, we will determine if genomic variants in ABCB1 are associated with the ratio of cerebrospinal fluid to plasma SSRI drug levels at the time of parturition. More than 90% of women treated at our institution receive combined spinal/epidural analgesia during labor and delivery and we propose to exploit this standard clinical practice to measure concentrations of SSRIs in simultaneously obtained plasma and CSF samples. We will then determine if genomic variants in ABCB1 correlate with the brain penetration of these drugs. Results from Specific Aim 3 will also contribute to investigating the whether CSF/plasma drug ratio can influence the pharmacodynamics of SSRIs in pregnancy.